An analysis has good news for patients with rheumatoid arthritis, or RA, who are concerned about the potential side effects of biologic disease-modifying antirheumatic drugs. A meta-analysis of 63 randomized controlled trials found that biologics taken on their own, or in combination with methotrexate, pose little increased risk of cancer, at least in the short term.

The largest meta-analysis to date on the much-debated subject, it adds to a growing body of evidence that biologics do not appear to significantly increase cancer risk. The findings were published in 2012 in the Journal of the American Medical Association (JAMA).

“This is a reassuring message,” says senior author Maria E. Suarez-Almazor, MD, PhD, a professor in the department of general internal medicine at The University of Texas MD Anderson Cancer Center, in Houston.

Dr. Suarez-Almazor acknowledges that many RA patients worry about side effects from taking biologics because the drugs suppress the immune system, which normally protects a person from disease and infection. The perceived threat of increased cancer risk is particularly alarming because RA patients in general have a slightly elevated risk of certain cancers – including lymphoma and lung cancer – although it’s not clear why.

Dr. Suarez-Almazor reviewed data from 63 clinical trials involving almost 30,000 patients who were followed for up to three years. Depending on the individual studies, control groups received either placebo or traditional disease-modifying antirheumatic drugs (such as methotrexate); other participants took any of the nine FDA-approved biologic medications – with or without methotrexate – for RA for at least six months. These include TNF-alpha inhibitors etanercept, or Enbrel; adalimumab, or Humira; certolizumab pegol, or Cimzia; golimumab, or Simponi; and infliximab, or Remicade. The other types of biologics studied were rituximab, or Rituxan; abatacept, or Orencia; tocilizumab, or Actemra; and anakinra, or Kineret.

The findings are promising. “What we found overall is that for biologics, in general, there appears to be very little risk or no risk at all with respect to cancer for about a year or so,” Dr. Suarez-Almazor explains.

Among the 3,615 patients taking only a biologic, researchers found a cancer risk of 0.64 percent. Among the 15,989 patients taking a biologic in combination with methotrexate, there was a cancer risk of 0.77 percent. And among the 9,819 patients in control groups, there was a cancer risk of 0.66 percent.

“The differences in these numbers are really very small and insignificant, not unlike small differences that happen just by chance,” Dr. Suarez-Almazor says.
 

Researchers also say that out of 9,711 patients, 0.08 percent who were treated with anti-TNFs developed lymphoma, compared with 0.04 percent of the 4,845 patients in the control groups. That indicates those on the anti-TNFs have double the risk of lymphoma, but researchers stress the number is not big enough to cause alarm.

“With anti-TNF agents, although there was a small trend, it was very small and did not reach statistical significance, so at this point it is not overly concerning,” Dr. Suarez-Almazor explains. “And for most of the different tests we did it was not present, so we can conclude there is probably very little risk, if any at all, for these agents in the short term.”

In the past, there have been manyquestions, concerns and conflicting data about cancer risk among arthritis patients taking anti-TNFs. This type of biologic has been around the longest and, consequently, has been studied the most. A September 2011 report, published online in the Annals of the Rheumatic Diseases, linked anti-TNFs to higher rates of skin cancer, although two other recent studies showed no cancer connection with the medications.

In 2009, the FDA recommended adding a warning label to all anti-TNFs concerning cancer risk in response to an increase in cases of spontaneous lymphoma among children and adolescents with juvenile idiopathic arthritis, or JIA, reported to the agency’s Adverse Events Reporting system database. But a study presented at the American College of Rheumatology 2010 Scientific Meeting challenged that, instead finding that JIA itself was the reason behind the increased cancer risk, not the anti-TNFs.

It is not expected to be the last word on the subject. “Trials last a year, so our study cannot tell us what happens after five, six or seven years. But at least it is reassuring that at the beginning of treatment, there does not appear to be an increase in cancer,” Dr. Suarez-Almazor says. 

Dr. Suarez-Almazor says more studies are being done to see the effects of the medications over time. “In the short term they are safe, but we may need to study them longer as they are used in the community and by thousands of patients to recognize if they have an effect with longer duration of treatment.”

David Fox, MD, chief of the division of rheumatology at the University of Michigan Health System in Ann Arbor, says although this isn’t new data, it’s helpful to see so many previously published studies analyzed together.

“It’s reassuring in terms of the early days of having a patient on biologics, but it doesn’t speak to late, long-term consequences,” he says.

Although the data about cancer risks for those on anti-TNFs in this study isn’t statistically significant, he still believes the evidence should have clinicians assuming that anti-TNFs can increase cancer rates, and he thinks they should pass this information on to patients.

“Patients should realize that powerful medications that can control a disease as aggressive as RA do come with the risk of side effects,” Dr. Fox says. “But these risks appear to be small enough that we can be comfortable using medications in patients who need them, and the benefit is likely to be much greater than the risk.”